Reduction In Stress Cracking Of Films

ABSTRACT

Methods and packages for storing film strips while reducing or eliminating stress cracking during storage, including use of packages having an inner surface made from polymeric materials exhibiting various physical properties and including films and pouches that are annealed.

FIELD OF THE INVENTION

The present invention relates to methods and packages for storing filmstrips while reducing or eliminating stress cracking during storage.

BACKGROUND OF THE INVENTION

Sporadic events of stress cracking in polymeric based film strips foundin finished products but not observed in a 15 minute in-process check orAQL testing has been an issue with some polymeric based film products.Stress cracking generally begins to appear in the film product 2 to 4weeks after manufacturing and packaging. Data analysis on lotsexhibiting cracking has led to the conclusion that the problem isprobably caused by imparting stress to the strips during themanufacturing process.

One source of stress that is imparted to the film during manufacturingis in the drying process. During drying, the wet film product is appliedor coated to a substrate, and is then dried on that substrate. In somedrying processes, particularly those including high solvent content, upto 70% of the volume of the wet film solution is removed in the dryingprocess. This shrinkage imparts stress to the film, which adheres to thesubstrate onto which it is cast and dried. Another source of stressinvolves the cutting process. Following the initial drying andshrinkage, typically the film product is cut into individual rolls orstrips. The film undergoes a number of bending operations as it transitsthe tortuous path of a slitting operation.

Finally, during fabrication and packaging of individual film strips, theprocess imparts additional stress by multiple turns around rollers,stripping the film off the substrate and by the pull wheels used to movethe film product through the converting/packaging machine. When thestrip is individually packaged in a material with a high surface energy,the film sticks to the packaging material and is not allowed to move torelieve the stresses. The stresses are thus relieved at a later time bystress cracking.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides methods for reducingor substantially reducing stress cracking of polymers in film products,such as edible film products including an active, by lowering thesurface energy of packaging materials.

In one embodiment, the present invention provides methods for reducingor substantially reducing stress cracking of polymers in film products,such as edible film products including an active, such as apharmaceutical active, by annealing the film prior to storing it in apouch or package.

In one embodiment, the present invention provides methods for reducingor substantially reducing stress cracking of polymers in film products,such as edible film including an active, such a pharmaceutical active,by annealing the pouch or package containing the film.

In one embodiment, the present invention provides methods for reducingor substantially reducing stress cracking of polymers in film products,such as edible film including an active, such as a pharmaceuticalactive, by both lowering the surface energy of packaging materials andby annealing the film prior to storing it in a pouch or package.

In one embodiment, the present invention reduces or substantiallyreduces stress cracking of polymers in film products, such as ediblefilm including an active, such a pharmaceutical active, by both loweringthe surface energy of packaging materials and by annealing the pouch orpackage in which the film product is stored.

In one embodiment, there is provided a package for storing a filmproduct including an active, such as a pharmaceutical active, including:(a) a top layer having an inner surface and an outer surface; and (b) abottom layer having an inner surface and an outer surface, the top layerand/or the bottom layer including a polymeric material, the innersurface of the top layer and/or the inner surface of the bottom layerhaving reduced adhesion to a film product, such as a film; wherein theinner surface of the top layer is partially sealed to the inner surfaceof the bottom layer, wherein a pocket is formed between the top layerand the bottom layer, and wherein a film product such as a film isstored within the pocket. Without wishing to be bound by any theory, theinner surface of the top layer and/or the inner surface of the bottomlayer has reduced adhesion to the film strip due to having (i) a surfaceenergy measured by a water contact angle test of about 100 degrees orgreater; and/or (ii) a surface adhesivity level of less than about 0.25lbf as measured by a peel force testing using a load frame and 1 inchwide packaging tape pulled at 2 inches/minute and averaged over adistance of 0.75 to 1.75 inches; and/or (iii) a surface RMS roughness ofless than 800 nm as measured by atomic force microscopy at a 100 micronsquare sample size square level.

In one embodiment, there is provided a package for storingpharmaceutical active containing film product, including: (a) a toplayer having an inner surface and an outer surface; and (b) a bottomlayer having an inner surface and an outer surface, the inner surface ofthe bottom layer including at least one polymeric material having atleast one physical characteristic selected from the group consisting of:(i) a surface energy measured by a water contact angle test of about 100degrees or greater, as; (ii) a surface adhesivity level of less thanabout 0.25 lbf as measured by a peel force testing using a load frameand 1 inch wide packaging tape pulled at 2 inches/minute and averagedover a distance of 0.75 to 1.75 inches; and (iii) a surface RMSroughness Root Mean Square (RMS) of less than 800 nm as measured byatomic force microscopy at a 100 micron square sample size level; wherethe inner surface of the top layer is partially sealed to the innersurface of the bottom layer, forming a pocket between the top layer andthe bottom layer.

In one embodiment, there is provided a method for reducing or preventingstress-cracking in a film product, including: providing a package forstoring pharmaceutical active containing film product, including: (a) atop layer having an inner surface and an outer surface; and (b) a bottomlayer having an inner surface and an outer surface, at least partiallysealing the inner surface of the top layer to the inner surface of thebottom layer to form a pocket therebetween, wherein the inner surface ofthe bottom layer includes at least one polymeric material having atleast one physical characteristic selected from the group consisting of:(i) a surface energy measured by a water contact angle test of about 100degrees or greater; and/or (ii) a surface adhesivity level of less thanabout 0.25 lbf as measured by a peel force testing using a load frameand 1 inch wide packaging tape pulled at 2 inches/minute and averagedover a distance of 0.75 to 1.75 inches; and/or (iii) a surface RMSroughness of less than 800 nm as measured by atomic force microscopy ata 100 micron square sample size level.

In one embodiment, there is provided a method for reducing stresscracking in a film including a continuous and uniform product includingthe steps of:

-   -   (a) preparing a film-forming matrix including a solvent, an        active and a polymeric material;    -   (b) forming a dried film by casting the film-forming matrix and        drying the film-forming matrix;    -   (c) annealing the dried film to relieve stresses imposed by the        drying process.

In one embodiment, there is provided a method for reducing stresscracking in a film, such as a film including a continuous and uniformproduct, including the steps of:

-   -   (a) preparing a film-forming matrix including a solvent, an        active and a polymeric material;    -   (b) forming a dried film by casting the film-forming matrix and        drying said film-forming matrix;    -   (c) packaging the dried film in a pouch    -   (d) annealing the pouched film to relieve stresses imposed by        the drying process.

In one embodiment, there is provided a reduced stress cracked filmproduct, such as a continuous and uniform film product, with reducedstress cracking, wherein the film product is formed by: casting afilm-forming matrix including a solvent, and active, and a polymericmaterial, drying the film-forming matrix to form a dried film, andannealing the dried film to relieve stress imposed by the dryingprocess. The film product has reduced stress cracking when the film isannealed compared to when the film is not annealed.

In one embodiment, there is provided a reduced stress cracked filmproduct, such as a continuous and uniform reduced stress cracked filmproduct, wherein the film product is formed by: casting a film-formingmatrix and drying the film-forming matrix to form a dried film;packaging the dried film into a pouch, and annealing the pouched film torelieve stresses imposed by the drying process. The pouched film hasreduced stress cracking when the film is annealed compared to when thefilm is not annealed.

In one embodiment, there is provided a pouch for storing a film productincluding an active, such as a pharmaceutical active, including alaminate of at least one first layer and at least one second layer,wherein the at least one first layer has an inner surface and an outersurface; wherein the second layer is positioned over the first layer;wherein the pouch includes a cavity including a film such as an ediblefilm including at least one polymer and including at least one active,such as a pharmaceutical active, positioned therein, and wherein thepouch is laminated. The pouch may be made from any suitable material,including suitable polymeric materials. The film is annealed to preventand/or reduce stress cracking in the film contained therein by applyingheat to the film. Thereafter, the film may be placed and stored in apouch or package in accordance with the present invention.

In one embodiment, there is provided a pouch for storing a film productincluding an active, such as a pharmaceutical active, including alaminate of at least one first layer and at least one second layer,wherein the at least one first layer has an inner surface and an outersurface; wherein the second layer is positioned over the first layer;wherein the pouch includes a cavity including a film which has beenannealed, such as an edible film which has been annealed and whichincludes at least one polymer and including at least one active, such asa pharmaceutical active, positioned therein, and wherein the pouch islaminated. The pouch may be made from any suitable material, includingsuitable polymeric materials.

In one embodiment, there is provided a method for reducing stresscracking in a film product comprising: (a) providing a sealed pouchincluding a laminate of at least one first layer and at least one secondlayer, wherein the at least one first layer has an inner surface and anouter surface; wherein the at least one second layer has an innersurface and an outer surface; wherein the second layer is positionedover said first layer; and wherein the pouch includes a cavity includingan edible film including at least one polymer and an active, such as apharmaceutical active, positioned therein, and (b) annealing the pouchto prevent and/or reduce stress-cracking in the film by applying heat tothe pouch.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the results of a comparative foil film peel test.

FIG. 2 shows the results of an AFM surface RMS roughness test forvarious films.

FIG. 3 shows the rate of stress cracking of films at various times.

FIG. 4 shows the rate of stress cracking of films after a sixty dayperiod.

FIG. 5 shows layers for use in forming a package or pouch of the presentinvention.

FIG. 6 is a cross sectional view of a package of the present invention.

FIG. 7 is a 2D birefringence map of a “fresh” (1 week old) film strip(shown at the top of FIG. 7) and “old” (3 week old) film strip (shown atthe bottom of FIG. 7) before anneal.

FIG. 8 is a 2D birefringence map of a “fresh” (1 week old) film strip(shown at the top of FIG. 8) and “old” (3 week old) film strip (shown atthe bottom of FIG. 8) after anneal.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “annealing” means a heat treatment that altersa material to, among other things, relieve internal stresses.

As used herein, the term “stress cracking” means a phenomena occurringin polymers, where the material is held together by a combination ofweaker Van der Waals forces and stronger covalent bonds. When sufficientlocal stress overcomes the Van der Waals force, a gap is formedresulting in a stress crack. These stress cracks can start as minutecracks, visible only under a microscope and depending on the stress inthe polymer, can with time separate a polymer film into 2 or morepieces. If the polymer film is left unrestrained, the stresses willrelieve themselves when the film is allowed to shrink. However, when thefilm is restrained by adhesion to a surface, the film cannot shrink andwill subsequently crack. Stress can also be relieved by annealing, whichallows relaxation of the stresses in the polymer and therefore preventsstress cracking.

As used herein, the terms “pharmaceutical”, “medicament”, “drug” and“active” may be used interchangeably, and refer to a substance orcomposition useful for the prevention or treatment of a condition. Theterms may include pharmaceuticals, neutraceuticals, cosmetic agents,biologic agents, bioeffective substances, and the like.

It will be understood that the terms “film” and “film strip” includedelivery systems of any thickness, including films and film strips,sheets, discs, wafers, and the like, in any shape, includingrectangular, square, or other desired shape. The film may be in the formof a continuous roll of film or may be sized to a desired length andwidth. The films described herein may be any desired thickness and sizesuitable for the intended use. For example, a film of the presentinvention may be sized such that it may be placed into the oral cavityof the user. Other films may be sized for application to the skin of theuser, i.e., a topical use. For example, some films may have a relativelythin thickness of from about 0.1 to about 10 mils, while others may havea somewhat thicker thickness of from about 10 to about 30 mils. For somefilms, especially those intended for topical use, the thickness may beeven larger, i.e., greater than about 30 mils. In addition, the term“film” includes single-layer compositions as well as multi-layercompositions, such as laminated films, coatings on films and the like.The composition in its dried film form maintains a uniform distributionof components through the processing of the film. Films may include apouch or region of medicament between two films. The films of thepresent invention may have any desired dimension suitable to provide thedesired level of active, and in some embodiments, the films have alength from about 10 to about 50 mm and a width of from about 10 toabout 50 mm, and may take any desired shape, including square andrectangle.

The term “patch” as used herein is intended to include multi-layeredfilm products, where the first layer (or “backing layer”) is a filmproduct that has a slower rate of dissolution than the second layer (or“active layer”). Patches described herein generally include the firstand second layers adhered or laminated to each other, where the secondlayer has a smaller length and/or width of the first layer, such that atleast a portion of the surface of the first layer is visible outside ofthe second layer.

Film strips may be formed through any desired processing means,including casting and drying methods as well as extrusion methods. Thefilm strips may be single-layer films or multiple layered films. Someexamples of methods of forming and drying films may be found in U.S.Pat. Nos. 7,425,292, 7,666,337, and 7,357,891, the contents of each ofwhich are incorporated by reference in their entireties. Any number ofactive components or pharmaceutical agents may be included in the filmsdiscussed herein. The active component(s) may be disposed within anylayer of film products formed herein or they may be placed onto one ormore surfaces of the film products.

Films formed by the present invention may be suitable for administrationto at least one region of the body of the user, such as mucosal regionsor regions within the body of the user, such as on the surface ofinternal organs. In some embodiments of the invention, the films areintended for oral administration. In other embodiments, the films areintended for topical administration. As used herein, the term “topicalagent” is meant to encompass active agents that are applied to aparticular surface area. For example, in one embodiment, a topical agentis applied to an area of the skin. In other embodiments, the topicalagent may also be applied to mucosal areas of the body, such as the oral(e.g., buccal, sublingual, tongue), vaginal, ocular and anal areas ofthe body. In still other embodiments, the topical agent is applied to aninternal organ or other body surface of the user, such as duringsurgery, where the agent may be removed or left within the body aftersurgery is complete. In other embodiments, a topical agent is applied toa hard surface, such as a particular surface area in need of treatment.In other embodiments, the films of the present invention are ingestible,and are intended to be placed in the mouth of the user and swallowed asthe film disintegrates.

The medicament may be dispersed throughout the film, or it may bedeposited onto one or more surfaces of the film. In either way, it isdesirable that the amount of medicament per unit area is substantiallyuniform throughout the film. The “unit area” is intended to include asuitable unit area, such as the area of one typical dosage unit. It isdesired that the films of the present invention include a uniformity ofcomponent distribution throughout the volume of a given film. That is,the individual film products (including individual dosages ofapproximately equal sizes) formed by the present invention should haveapproximately the same content composition as each other film product.Such uniformity includes a substantially uniform amount of medicamentper unit volume of the film, whether the medicament is within the matrixof the film or coated, laminated, or stabilized on one or more surfacesthereof. When such films are cut into individual units, the amount ofthe agent in the unit can be known with a great deal of accuracy. Forthe films formed herein, it is understood by one of ordinary skill inthe art that the resulting film is not required to be exactly 100%uniform. All that is required is that the film be “substantiallyuniform”, i.e., a slight amount of non-uniformity is understood to beacceptable. “Substantially uniform” may include, for example, a filmthat is about 90% uniform in content from one region of the film toanother, or a film that is about 95% uniform in content from one regionof the film to another, and most desirably about 99% uniform in contentfrom one region of the film to another. In other words, “substantiallyuniform” may mean that individual film products should vary by no morethan about 10% with respect to each other. In some embodiments,“substantially uniform” may mean that individual film products shouldvary by no more than about 5% with respect to each other.

After formation of the film, a plurality of film strips having similardimensions, including length, width and depth, may be cut from the filmproduct. Each film strip is desirably substantially uniform in contentfrom each other, particularly in active content. When forming films, theuser sets a target active content, depending upon the desired level ofactive in the film. That target content is referred to as 100% of thetarget level. For example, the desired film strip may desirably have 1mg of active per unit dose, and thus 1 mg would be the “target content”.Each substantially similarly sized film strip cut from the film productshould be within about 10% of that target content. More desirably, eachsubstantially similarly sized film strip cut from the film productshould be within about 8% of the target content, or within 6% of thetarget content, or within 4% of the target content. For a target contentof 1.0 mg per unit dose, substantially uniform films may have from about0.90 mg to about 1.10 mg per unit dose. When an active is introduced tothe film, the amount of active per unit area is determined by theuniform distribution of the film. For example, when the films are cutinto individual dosage forms, the amount of the active in the dosageform can be known with a great deal of accuracy. This is achievedbecause the amount of the active in a given area is substantiallyidentical to the amount of active in an area of the same dimensions inanother part of the film. The accuracy in dosage is particularlyadvantageous when the active is a medicament, i.e. a drug.

The active components that may be incorporated into the films of thepresent invention include, without limitation pharmaceutical andcosmetic actives, drugs, medicaments, proteins, antigens or allergenssuch as ragweed pollen, spores, microorganisms, seeds, mouthwashcomponents, flavors, fragrances, enzymes, preservatives, sweeteningagents, colorants, spices, vitamins and combinations thereof.

A wide variety of medicaments, bioactive active substances andpharmaceutical compositions may be included in the dosage forms of thepresent invention. Examples of useful drugs include ace-inhibitors,antianginal drugs, anti-arrhythmias, anti-asthmatics,anti-cholesterolemics, analgesics, anesthetics, anti-convulsants,anti-depressants, anti-diabetic agents, anti-diarrhea preparations,antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatoryagents, anti-lipid agents, anti-manics, anti-nauseants, anti-strokeagents, anti-thyroid preparations, anti-tumor drugs, anti-viral agents,acne drugs, alkaloids, amino acid preparations, anti-tussives,anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemicand non-systemic anti-infective agents, anti-neoplastics,anti-parkinsonian agents, anti-rheumatic agents, appetite stimulants,biological response modifiers, blood modifiers, bone metabolismregulators, cardiovascular agents, central nervous system stimulates,cholinesterase inhibitors, contraceptives, decongestants, dietarysupplements, dopamine receptor agonists, endometriosis managementagents, enzymes, erectile dysfunction therapies, fertility agents,gastrointestinal agents, homeopathic remedies, hormones, hypercalcemiaand hypocalcemia management agents, immunomodulators,immunosuppressives, migraine preparations, motion sickness treatments,muscle relaxants, obesity management agents, osteoporosis preparations,oxytocics, parasympatholytics, parasympathomimetics, prostaglandins,psychotherapeutic agents, respiratory agents, sedatives, smokingcessation aids, sympatholytics, tremor preparations, urinary tractagents, vasodilators, laxatives, antacids, ion exchange resins,anti-pyretics, appetite suppressants, expectorants, anti-anxiety agents,anti-ulcer agents, anti-inflammatory substances, coronary dilators,cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants,anti-hypertensive drugs, vasoconstrictors, migraine treatments,antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs,anti-coagulants, anti-thrombotic drugs, hypnotics, anti-emetics,anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- andhypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics,anti-spasmodics, terine relaxants, anti-obesity drugs, erythropoieticdrugs, anti-asthmatics, cough suppressants, mucolytics, DNA and geneticmodifying drugs, and combinations thereof.

Examples of medicating active ingredients contemplated for use in thepresent invention include antacids, H₂-antagonists, and analgesics. Forexample, antacid dosages can be prepared using the ingredients calciumcarbonate alone or in combination with magnesium hydroxide, and/oraluminum hydroxide. Moreover, antacids can be used in combination withH₂-antagonists.

Analgesics include opiates and opiate derivatives, such as oxycodone(available as Oxycontin®), ibuprofen, aspirin, acetaminophen, andcombinations thereof that may optionally include caffeine.

Other preferred drugs for other preferred active ingredients for use inthe present invention include anti-diarrheals such as immodium AD,anti-histamines, anti-tussives, decongestants, vitamins, and breathfresheners. Common drugs used alone or in combination for colds, pain,fever, cough, congestion, runny nose and allergies, such asacetaminophen, chlorpheniramine maleate, dextromethorphan,pseudoephedrine HCl and diphenhydramine may be included in the filmcompositions of the present invention.

Also contemplated for use herein are anxiolytics such as alprazolam(available as Xanax®); anti-psychotics such as clozopin (available asClozaril®) and haloperidol (available as Haldol®); non-steroidalanti-inflammatories (NSAID's) such as dicyclofenacs (available asVoltaren®) and etodolac (available as Lodine®), anti-histamines such asloratadine (available as Claritin®), astemizole (available asHismanal™), nabumetone (available as Relafen®), and Clemastine(available as Tavist®); anti-emetics such as granisetron hydrochloride(available as Kytril®) and nabilone (available as Cesamet™);bronchodilators such as Bentolin®, albuterol sulfate (available asProventil®); anti-depressants such as fluoxetine hydrochloride(available as Prozac®), sertraline hydrochloride (available as Zoloft®),and paroxtine hydrochloride (available as Paxil®); anti-migraines suchas Imigra®, ACE-inhibitors such as enalaprilat (available as Vasotec®),captopril (available as Capoten®) and lisinopril (available asZestril®); anti-Alzheimer's agents, such as nicergoline; andCa^(H)-antagonists such as nifedipine (available as Procardia® andAdalat®), and verapamil hydrochloride (available as Calan®).

Erectile dysfunction therapies include, but are not limited to, drugsfor facilitating blood flow to the penis, and for effecting autonomicnervous activities, such as increasing parasympathetic (cholinergic) anddecreasing sympathetic (adrenersic) activities. Useful non-limitingdrugs include sildenafils, such as Viagra®, tadalafils, such as Cialis®,vardenafils, apomorphines, such as Uprima®, yohimbine hydrochloridessuch as Aphrodyne®, and alprostadils such as Caverject®.

The popular H₂-antagonists which are contemplated for use in the presentinvention include cimetidine, ranitidine hydrochloride, famotidine,nizatidien, ebrotidine, mifentidine, roxatidine, pisatidine andaceroxatidine.

Active antacid ingredients include, but are not limited to, thefollowing: aluminum hydroxide, dihydroxyaluminum aminoacetate,aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, bismuthsubsilysilate, calcium carbonate, calcium phosphate, citrate ion (acidor salt), amino acetic acid, hydrate magnesium aluminate sulfate,magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesiumglycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate,milk solids, aluminum mono- or di-basic calcium phosphate, tricalciumphosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate,magnesium aluminosilicates, tartaric acids and salts. Thepharmaceutically active agents employed in the present invention mayinclude allergens or antigens, such as, but not limited to, plantpollens from grasses, trees, or ragweed; animal danders, which are tinyscales shed from the skin and hair of cats and other furred animals;insects, such as house dust mites, bees, and wasps; and drugs, such aspenicillin.

An anti-oxidant may also be added to the film to prevent the degradationof an active, especially where the active is photosensitive.

Cosmetic active agents may include breath freshening compounds likementhol, other flavors or fragrances, especially those used for oralhygiene, as well as actives used in dental and oral cleansing such asquaternary ammonium bases. The effect of flavors may be enhanced usingflavor enhancers like tartaric acid, citric acid, vanillin, or the like.

Also color additives can be used in preparing the films. Such coloradditives include food, drug and cosmetic colors (FD&C), drug andcosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).These colors are dyes, their corresponding lakes, and certain naturaland derived colorants. Lakes are dyes absorbed on aluminum hydroxide.Other examples of coloring agents include known azo dyes, organic orinorganic pigments, or coloring agents of natural origin. Inorganicpigments are preferred, such as the oxides or iron or titanium, theseoxides, being added in concentrations ranging from about 0.001 to about10%, and preferably about 0.5 to about 3%, based on the weight of allthe components. Flavors may be chosen from natural and syntheticflavoring liquids. An illustrative list of such agents includes volatileoils, synthetic flavor oils, flavoring aromatics, oils, liquids,oleoresins or extracts derived from plants, leaves, flowers, fruits,stems and combinations thereof. A non-limiting representative list ofexamples includes mint oils, cocoa, and citrus oils such as lemon,orange, grape, lime and grapefruit and fruit essences including apple,pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple,apricot or other fruit flavors.

The films containing flavorings may be added to provide a hot or coldflavored drink or soup. These flavorings include, without limitation,tea and soup flavorings such as beef and chicken.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime),neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon),aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehydeC-12 (citrus fruits), tolyl aldehyde (cherry, almond),2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin),combinations thereof and the like.

The film products of the present invention are capable of accommodatinga wide range of amounts of the active ingredient. The films are capableof providing an accurate dosage amount (determined by the size of thefilm and concentration of the active in the original polymer/watercombination) regardless of whether the required dosage is high orextremely low. Therefore, depending on the type of active orpharmaceutical composition that is incorporated into the film, theactive amount may be as high as about 300 mg, desirably up to about 150mg or as low as the microgram range, or any amount therebetween.

Sweeteners for us in the present invention may be chosen from thefollowing non-limiting list: glucose (corn syrup), dextrose, invertsugar, fructose, and combinations thereof; saccharin and its varioussalts such as the sodium salt; dipeptide sweeteners such as aspartame;dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside);chloro derivatives of sucrose such as sucralose; sugar alcohols such assorbitol, mannitol, xylitol, and the like. Also contemplated arehydrogenated starch hydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof, and natural intensive sweeteners, such as Lo Han Kuo.Other sweeteners may also be used.

The film products and methods of the present invention are well suitedfor high potency, low dosage drugs. This is accomplished through thehigh degree of uniformity of the films. Therefore, low dosage drugs,particularly more potent racemic mixtures of actives are desirable. Thepolymer may be water soluble, water swellable, water insoluble, or acombination of one or more either water soluble, water swellable orwater insoluble polymers. The polymer may include cellulose or acellulose derivative. Specific examples of useful water soluble polymersinclude, but are not limited to, polyethylene oxide (PEO), pullulan,hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HPC),hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose,polyvinyl alcohol, sodium aginate, polyethylene glycol, xanthan gum,tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid,methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin,and combinations thereof. Specific examples of useful water insolublepolymers include, but are not limited to, ethyl cellulose, hydroxypropylethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate and combinations thereof.

As used herein the phrase “water soluble polymer” and variants thereofrefer to a polymer that is at least partially soluble in water, anddesirably fully or predominantly soluble in water, or absorbs water.Polymers that absorb water are often referred to as being waterswellable polymers. The materials useful with the present invention maybe water soluble or water swellable at room temperature and othertemperatures, such as temperatures exceeding room temperature. Moreover,the materials may be water soluble or water swellable at pressures lessthan atmospheric pressure. Desirably, the water soluble polymers arewater soluble or water swellable having at least 20 percent by weightwater uptake. Water swellable polymers having a 25 or greater percent byweight water uptake are also useful. Films or dosage forms of thepresent invention formed from such water soluble polymers are desirablysufficiently water soluble to be dissolvable upon contact with bodilyfluids.

Other polymers useful for incorporation into the films of the presentinvention include biodegradable polymers, copolymers, block polymers andcombinations thereof. Among the known useful polymers or polymer classeswhich meet the above criteria are: poly(glycolic acid) (PGA),poly(lactic acid) (PLA), polydioxanoes, polyoxalates, poly(α-esters),polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters),polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates,polyamides, poly(alkyl cyanoacrylates), and mixtures and copolymersthereof. Additional useful polymers include, stereopolymers of L- andD-lactic acid, copolymers of bis(p-carboxyphenoxy) propane acid andsebacic acid, sebacic acid copolymers, copolymers of caprolactone,poly(lactic acid)/poly(glycolic acid)/polyethyleneglycol copolymers,copolymers of polyurethane and (poly(lactic acid), copolymers ofpolyurethane and poly(lactic acid), copolymers of α-amino acids,copolymers of α-amino acids and caproic acid, copolymers of α-benzylglutamate and polyethylene glycol, copolymers of succinate andpoly(glycols), polyphosphazene, polyhydroxy-alkanoates and mixturesthereof. Binary and ternary systems are contemplated.

Other specific polymers useful include those marketed under the Medisorband Biodel trademarks. The Medisorb materials are marketed by the DupontCompany of Wilmington, Del. and are generically identified as a“lactide/glycolide co-polymer” containing “propanoic acid,2-hydroxy-polymer with hydroxy-polymer with hydroxyacetic acid.” Foursuch polymers include lactide/glycolide 100 L, believed to be 100%lactide having a melting point within the range of 338°-347° F.(170°-175° C.); lactide/glycolide 100 L, believed to be 100% glycolidehaving a melting point within the range of 437°-455° F. (225°-235° C.);lactide/glycolide 85/15, believed to be 85% lactide and 15% glycolidewith a melting point within the range of 338°-347° F. (170°-175° C.);and lactide/glycolide 50/50, believed to be a copolymer of 50% lactideand 50% glycolide with a melting point within the range of 338°-347° F.(170°-175° C.).

The Biodel materials represent a family of various polyanhydrides whichdiffer chemically.

Although a variety of different polymers may be used, it is desired toselect polymers to provide a desired viscosity of the mixture prior todrying. For example, if the active or other components are not solublein the selected solvent, a polymer that will provide a greater viscosityis desired to assist in maintaining uniformity. On the other hand, ifthe components are soluble in the solvent, a polymer that provides alower viscosity may be preferred.

The polymer plays an important role in affecting the viscosity of thefilm. Viscosity is one property of a liquid that controls the stabilityof the active in an emulsion, a colloid or a suspension. Generally theviscosity of the matrix will vary from about 400 cps to about 100,000cps, preferably from about 800 cps to about 60,000 cps, and mostpreferably from about 1,000 cps to about 40,000 cps. Desirably, theviscosity of the film-forming matrix will rapidly increase uponinitiation of the drying process.

The viscosity may be adjusted based on the selected active depending onthe other components within the matrix. For example, if the component isnot soluble within the selected solvent, a proper viscosity may beselected to prevent the component from settling which would adverselyaffect the uniformity of the resulting film. The viscosity may beadjusted in different ways. To increase viscosity of the film matrix,the polymer may be chosen of a higher molecular weight or crosslinkersmay be added, such as salts of calcium, sodium and potassium. Theviscosity may also be adjusted by adjusting the temperature or by addinga viscosity increasing component. Components that will increase theviscosity or stabilize the emulsion/suspension include higher molecularweight polymers and polysaccharides and gums, which include withoutlimitation, alginate, carrageenan, hydroxypropyl methyl cellulose,locust bean gum, guar gum, xanthan gum, dextran, gum arabic, gellan gumand combinations thereof.

It has also been observed that certain polymers which when used alonewould ordinarily require a plasticizer to achieve a flexible film, canbe combined without a plasticizer and yet achieve flexible films. Forexample, HPMC and HPC when used in combination provide a flexible,strong film with the appropriate plasticity and elasticity formanufacturing and storage. No additional plasticizer or polyalcohol isneeded for flexibility.

Additionally, polyethylene oxide (PEO), when used alone or incombination with a hydrophilic cellulosic polymer, achieves flexible,strong films. Additional plasticizers or polyalcohols are not needed forflexibility. Non-limiting examples of suitable cellulosic polymers forcombination with PEO include HPC and HPMC. PEO and HPC have essentiallyno gelation temperature, while HPMC has a gelation temperature of 58-64°C. (Methocel EF available from Dow Chemical Co.). Moreover, these filmsare sufficiently flexible even when substantially free of organicsolvents, which may be removed without compromising film properties. Assuch, if there is no solvent present, then there is no plasticizer inthe films. PEO based films also exhibit good resistance to tearing,little or no curling, and fast dissolution rates when the polymercomponent contains appropriate levels of PEO.

To achieve the desired film properties, the level and/or molecularweight of PEO in the polymer component may be varied. Modifying the PEOcontent affects properties such as tear resistance, dissolution rate,and adhesion tendencies. Thus, one method for controlling filmproperties is to modify the PEO content. For instance, in someembodiments rapid dissolving films are desirable. By modifying thecontent of the polymer component, the desired dissolutioncharacteristics can be achieved.

In accordance with the present invention, PEO desirably ranges fromabout 20% to 100% by weight in the polymer component. In someembodiments, the amount of PEO desirably ranges from about 1 mg to about200 mg. The hydrophilic cellulosic polymer ranges from about 0% to about80% by weight, or in a ratio of up to about 4:1 with the PEO, anddesirably in a ratio of about 1:1.

In some embodiments, it may be desirable to vary the PEO levels topromote certain film properties. To obtain films with high tearresistance and fast dissolution rates, levels of about 50% or greater ofPEO in the polymer component are desirable. To achieve adhesionprevention, i.e., preventing the film from adhering to the roof of themouth, PEO levels of about 20% to 75% are desirable. In someembodiments, however, adhesion to the roof of the mouth may be desired,such as for administration to animals or children. In such cases, higherlevels of PEO may be employed. More specifically, structural integrityand dissolution of the film can be controlled such that the film canadhere to mucosa and be readily removed, or adhere more firmly and bedifficult to remove, depending on the intended use.

The molecular weight of the PEO may also be varied. High molecularweight PEO, such as about 4 million, may be desired to increasemucoadhesivity of the film. More desirably, the molecular weight mayrange from about 100,000 to 900,000, more desirably from about 100,000to 600,000, and most desirably from about 100,000 to 300,000. In someembodiments, it may be desirable to combine high molecular weight(600,000 to 900,000) with low molecular weight (100,000 to 300,000) PEOsin the polymer component.

For instance, certain film properties, such as fast dissolution ratesand high tear resistance, may be attained by combining small amounts ofhigh molecular weight PEOs with larger amounts of lower molecular weightPEOs. Desirably, such compositions contain about 60% or greater levelsof the lower molecular weight PEO in the PEO-blend polymer component.

To balance the properties of adhesion prevention, fast dissolution rate,and good tear resistance, desirable film compositions may include about50% to 75% low molecular weight PEO, optionally combined with a smallamount of a higher molecular weight PEO, with the remainder of thepolymer component containing a hydrophilic cellulosic polymer (HPC orHPMC).

Desirably, the films of the present invention include polyethylene oxide(PEO), hydroxypropylmethylcellulose or a combination thereof.

The layers of the packages and pouches of the present invention mayinclude any suitable packaging material. Desirably, low densitypolyethylene (LDPE) and/or ethylene acrylic acid may be product contactlayers in packaging material. Once a film strip is formed and cut to theappropriate and desired size, the film strip is packaged. Packaging offilm strips helps keep the film strips in a controlled environment so asto maintain the integrity of the film strip and the active content.Desirably, a single package houses one single film strip and is sealedso that the film strip is not exposed to an external environment.Typically, film strip packages are made from foil, polymeric materials,or combinations of foil and polymeric materials. In some embodiments,the package is made from at least one laminated foil, where the foil islaminated with a polymeric material. The package is capable of beingopened by the user by one or more known methods, including, for example,tear notches, perforations, or through use of a tool such as scissors orother blade.

A representative package suitable for the present invention is shown inFIG. 6. A top layer 20 including an outer surface 20A and a bottomsurface 20B and a bottom layer 30 including an outer surface 30A and abottom layer 30A for use in making the package are shown in FIG. 5. Asshown in FIG. 6, the package 10 includes a top layer 20 and bottom layer30. The top layer 20 includes an outer surface 20A that is exposed tothe outside environment, and an inner surface 20B that is in contactwith an interior pocket 40 of the package 10. The bottom layer 30 alsoincludes an outer surface 30A that is exposed to the outside environmentand an inner surface 30B that is in contact with the interior pocket 40of the package. A film strip 50 is contained within the interior pocket40 of the package 10. The package 10 may be oriented in any direction,but for ease of explanation FIG. 6 shows the bottom layer 30 under thetop surface 20, such that the film strip 50 rests on the inner surface30A of the bottom layer 30. It is understood that in some embodiments,the film strip 50 may be in at least partial contact with the innersurface 20A of the top layer 20. Since the film strip 50 is or may be incontact with the inner surfaces 20A, 30A of the package 10, the innersurfaces 20A, 30A of the package 10 should be made from a material ormaterials that are inert with respect to the film strip 50. Thematerials forming the inner surfaces 20A, 30A of the package 10 shouldnot be capable of reacting with the film strip 50 so as to affect thefilm strip 50 in a material way.

After cutting the film strip to the proper and desired size, it isplaced onto the inner surface 30A of the package 10, and the package 10is then closed around the film strip 50 and sealed. The film strip 50may remain in the package 10 for an extended period of time, and may bewithin the package 10 for days, weeks, months, or even years. In someembodiments, the package 10 is suitable to house the film strip 50without detrimental damage to the film strip 50 for at least 1 week, orfor at least 1 month, or for at least 6 months, or for at least 1 year.In some embodiments, the film strip 50 suitably remains in the package10 for about 1 month to about 2 years without detrimental damage. Insome embodiments, the film strip 50 suitably remains in the package 10for about 1 month to about 2 years without detrimental damage.

In some embodiments, the film may be formed directly onto the innersurface of the package during the manufacturing stage. In suchembodiments, the film strip is formed at the desired dimensions, smallerthan the package.

When a user wishes to use the film strip, the user opens the package andremoves the film strip. It is important that the film strip not stick toor adhere to the inner surface of the package, so as to allow for easyremoval of the film strip. However, in addition to the ease of removalof the film strip, the present inventors have discovered that the innersurface of the package should be made from a material that resistsformation of stress cracking in the film strip. This is particularlytrue when the film strip is made from a polymeric material or materialsthat are susceptible to stress cracking. As will be discussed below, theinner surface of the package desirably is made from a material ormaterials having a low surface energy. In addition, the inner surfacemay have a lower surface adhesivity with respect to the film strip thatis housed in the package. Also, or in the alternative, the inner surfacemay have a lower root mean square surface roughness, as measured at the100 micron square sample size scale. Each of these properties isdiscussed below.

Stress cracking of films is particularly noticeable when certainpolymers are used in the film product. Such polymers include polymersthat are or can become highly crystalline in nature. One particularlynoticeable polymer that causes stress cracking is polyethylene oxide(PEO). However, polymeric materials such as PEO offer a number ofadvantages in a film product, and thus it is desirable to use PEO andsimilar materials, either alone or in combination with other polymericcomponents, in the formation of films. For example, PEO may be used incombination with a cellulosic material, such as HPC or HPMC.Unfortunately, due to its tendency to cause stress cracking, PEO hasbeen found to cause problems when the user wishes to use the film. Assuch, certain measures should be taken during the preparation andpackaging of the film strips. One such measure is to use packagingmaterials that include an inner surface made from a material ormaterials that will reduce the likelihood of stress cracking. Desirablematerials include those that have at least one of the followingcharacteristics: the inner surface of the package being made from amaterial or materials having a low surface energy; the inner surfacehaving a lower surface adhesivity with respect to the film strip that ishoused in the package; and the inner surface having a lower root meansquare surface roughness, as measured at the 100 micron square samplesize scale.

It has been noticed by the present inventors that films including PEO aseither the sole or as one of the polymeric materials in the film cansuffer from stress cracking. Such films have suffered from stresscracking even on a number of different packaging materials. Stresscracking is undesirable as it has an unappealing appearance, thuscausing the user of the film strip to question its integrity andusefulness. The present inventors have noticed that films including PEOas a polymeric component tended to adhere to various packagingmaterials, thus causing more stress cracking as observed when thepackage was opened. One such packaging material that demonstratednoticeable stress cracking in films was a material having an innersurface made from ethylene acrylic acid. Up to 63% of films that wereprepared on such packaging materials demonstrated stress cracking.

The present inventors have discovered, however, that a film includingpolymers that are or can become highly crystalline in nature as apolymeric component can be formed without stress cracking when stored ona packaging material made from a material having a lower surface energy,having lower surface adhesivity, or having a lower surface roughness.The surface energy of a product may be measured by a water contact angletest, described below. The desired surface energy is about 100 degreesor greater, as measured by the water contact angle test.

Surface adhesivity may be measured by peel force testing using a loadframe and packaging tape. Using such a test, the desired surface has anaverage peel force of less than about 0.25 lbf, and more desirably lessthan about 0.20 lbf. Finally, surface RMS roughness may be measured byatomic force microscopy at a 100 micron square sample size level. At the100 micron square sample size level, the desired surface RMS roughnessof the package material should be less than about 800 nm, and desirablyless than about 700 nm.

One such packaging material having a lower surface energy includesmaterials made from low density polyethylene (LDPE). When the innersurface of the package is made from a material including LDPE, the filmstrips were found to have reduced or eliminated stress cracking. Suchinner surfaces have a surface energy of about 100 degrees or greater asmeasured by the water contact angle test, a surface adhesivity of about0.25 lbf or less as measured by peel force testing, and a surface RMSroughness of about 800 nm or less as measured by atomic force microscopyat a 100 micron square sample size level.

Desirably, less than 10% of film strips stored in the inventive packageexhibit stress cracking after storage of about three months attemperatures of about 25° C. to about 30° C.

Surface roughness was measured using Atomic force microscopy (AFM). AFMscans were completed with three scans of each film, one 100 μm square,one 25 μm square, and one 5 μm square. As the scan size decreases, thelateral resolution of the images increases, allowing the small scansizes to make out smaller features.

Water contact angle tests were conducted by applying a 5 microliter dropof purified water on the film using a micro-pipette. Images were takenof each drop and image processing was used to capture the shape of eachdrop's surface, and the data was processed to calculate the contactangle.

Peel tests were conducted with packaging tape applied to sampled films.Test samples were one inch wide. The ends of the tape and the substratefilms were clamped by grips of an MTS load frame (tensile tester),manufactured by MTS Systems Corporation. The tests were run at 2 inchesper minute speed. The load rises as the specimen ends are pulled untilthe sample is taught and peeling progresses. Once peeling is initiated,the load is variable, based on the local bond strength between packagingtape and the substrate film. The data became more stable after amoderate opening length, and the test data was averaged over on openingdistance of 0.75 inches to 1.75 inches.

In some embodiments, additives may optionally be included in the filmsof the present invention to assist in ameliorating internal stresses inthe film structure. Such additives may include, for example,surfactants, plasticizers, and vitamin E, TPGS, and combinationsthereof. Such additives may be present in any suitable amount. Suitableamounts of such additives include, for example, from about 1% by weightto about 50% or higher by weight of a film. In some embodiments, aplasticizer may be present in an amount from about 5% by weight to about30% by weight of a film. In some embodiments, a plasticizer may bepresent in an amount from about 2% by weight to about 30% by weight of afilm. In some embodiments, a plasticizer may be present in an amount ofabout 5% by weight of a film.

The present invention also reduces the tendency and likelihood of stresscracking through certain measures taken in the packaging stage offormation.

In some embodiments, a film may be annealed to reduce or substantiallyreduce stress cracking in the film prior to being stored in a package orpouch. In some embodiments, a film is annealed at a temperature between40 degrees C. and 90 degrees C. In some embodiments, the film isannealed at a time between 0.5 minutes and 60 minutes.

In some embodiments, a film is annealed by removing the film from asubstrate, annealing the film and rewinding the film onto a substrate.In some embodiments, a film is annealed at a temperature between 40degrees C. and 90 degrees C. In some embodiments, a film is annealed ata time between 0.5 minutes and 60 minutes In some embodiments, a film isintact with no cracking after 3 weeks in a package.

In some embodiments, a film is intact with no cracking after 2 months ina package. In some embodiments, a film is intact with no cracking after6 months in a package. In some embodiments, a film is intact with nocracking after 12 months in a package. In some embodiments, a film isintact with no cracking after 2 years in a package. In some embodiments,a film is intact with no cracking after 3 years in a package. In someembodiments, a film is intact with no cracking after 3 weeks in apackage. In some embodiments, a film is intact with no cracking after 2months in a package. In some embodiments, a film is intact with nocracking after 6 months in a package. In some embodiments, a film isintact with no cracking after 12 months in a package. In someembodiments, a film is intact with no cracking after 2 years in apackage. In some embodiments, a film is intact with no cracking after 3years in a package.

In some embodiments, a package or pouch including a film product, suchas a polymeric film, may be annealed to prevent and/or reducestress-cracking in the film. In some embodiments, the package or pouchincluding the product is annealed by placing the sealed pouches of theproduct in an oven. The package or pouch may be heat annealed for anysuitable length of time, including from about 0.5 to about 120 minutes.Moreover, the package or pouch may be annealed at any suitabletemperature, including from about 40° C. to about 90° C. In someembodiments, the packaged film is annealed at a temperature between 40degrees C. and 90 degrees C.

Desirably, a package or pouch of the present invention is heat annealedat 70° C. for 25 minutes. In some embodiments, a packaged film isannealed at a time between about 0.5 minutes and about 60 minutes. Insome embodiments, a packaged film is annealed at a time between 0.5minutes and 60 minutes.

EXAMPLES Example 1 Comparative Testing Between Two Materials

Two materials were tested for peel force using a load frame andpackaging tape. The first material (“Material A”) was a packagingproduct having a surface made from ethylene acrylic acid, and the secondmaterial (“Material B”) was a packaging product having a surface madefrom LDPE. FIG. 1 demonstrates the foil film peel test results for thesetwo materials.

Test samples were one inch wide. The ends of the tape and the substratefilms were clamped by grips of an MTS load frame. The tests were run at2 inches per minute speed. The load rises as the specimen ends arepulled until the sample is taught and peeling progresses. Once peelingis initiated, the load is variable based on the local bond strengthbetween packaging tape and the substrate film. The data became morestable after a moderate opening length, and the test data was averagedover on opening distance of 0.75 inches to 1.75 inches.

Water contact angle tests were then run on the surfaces of the twomaterials. These tests were conducted by applying a 5 microliter drop onthe product contact surface using a micro-pipette. Images were taken ofeach drop, and image processing was used to capture the shape of eachdrop's surface, and the data was processed to calculate the contactangle.

Film contact angle results show that Material B, having a surface madefrom LDPE, demonstrated the highest contact angle and therefore thelowest surface energy of the materials tested. The higher surface energyof Material A (having a surface made from ethylene acrylic acid) resultsin better wet-out and a greater tendency for other materials (e.g. filmstrips) to stick to the surface. This is again consistent withobservations that film strips tend to stick to Material A. The resultsare set forth in Table 1 below:

TABLE 1 Film Contact Angle Results Sample Contact Angle (deg) Material A95.6 95.4 88.9 89.2 88 89.3 Material B 100.7 104.7 106.8 109.5 109.2106.3

Atomic force microscope (AFM) scans were completed on both films to gainadditional insight into the physical structure of each. Three scans ofeach film, one 100 μm square, one 25 μm square, and one 5 μm square weredone. As the scan size decreases, the lateral resolution of the imagesincreases, allowing the small scan sizes to make out smaller features.FIG. 2 shows the AFM surface RMS roughness of the films.

The results indicate that at the 100 micron square same size scale, theMaterial A shows the highest surface roughness, approximately 30% morerough than Material B. This is consistent with the Material A havinghigher surface energy and higher adhesivity to other materials. The datathen can be summarized as the peel force testing, contact anglemeasurement and surface RMS roughness measurements by AFM all suggestthat the Material A packaging material has a higher surface adhesivity(peel force), a higher surface energy (lower contact angle) and a highersurface RMS roughness at a 100 micron square sample size scale.

These results are consistent with observations that film strips areoften found sticking to Material A when opened for examination. It isbelieved that this tendency to stick to Material A is directly relatedfor the film strips' tendency to crack while in the Material A package.The results are also consistent with the observation that the filmstrips have seldom been found to stick to the Material B and the stripsexperience much less stress cracking when packaged in this material.Since Material B has a lower surface energy and roughness, the strips donot tend to stick and subsequently crack when packaged into thismaterial.

Example 2 Comparative Testing

Two lots of film product, both including PEO as a polymeric component,were manufactured and packaged in two separate packaging materials. Thefirst packaging material included an inner surface made from ethyleneacrylic acid and the second packaging material included an inner surfacemade from LDPE. These lots were inspected after 20 weeks for stresscracked strips.

After twenty weeks, the first lot packaged in the ethylene acrylic acidpackaging showed 30.4% stress cracking, and the first lot packaged inthe LDPE packaging showed 4.2% stress cracking. Also after twenty weeks,the second lot packaged in the ethylene acrylic acid packaging showed46.4% stress cracking, and the first lot packaged in the LDPE packagingshowed 0% stress cracking.

Example 3 Use of LDPE Packaging Material

Five lots of film material, each including PEO as a polymeric component,were packaged in a packaging material including an inner surface madefrom LDPE and placed in a 36 month stability program. The samples werestored at either 25° C. or 30° C. At the end of the 36 months, sampleswere inspected for stress cracking. The results are presented in Table 2below:

TABLE 2 Stress cracking after 36 months storage at different temperatureconditions. Storage temperature Percentage with Lot No. Number ofSamples (° C.) Stress Cracking 1 25 25 0% 2 25 25 0% 3 25 25 0% 4 25 250% 5 25 25 0% 1 25 30 0% 2 25 30 0% 3 25 30 0% 4 25 30 0% 5 25 30 0%

Example 4 Use of LDPE Packaging Material

Nine lots of three different strengths of film, each including PEO, weremanufactured and packaged in a packaging material having an innersurface made from LDPE. The films were inspected for stress crackingafter 5 months. The results are shown in Table 3 below:

TABLE 3 Frequency of stress cracking in experimental lots. Lot No.Percentage with Stress Cracking 1 0% 2 0% 3 0% 4 0% 5 0% 6 0.67%   70.20%   8 0% 9 0%

Example 5 Comparative Testing

Twelve lots of film, each including PEO as a polymeric component, werepackaged in a packaging material having an inner surface made fromethylene acrylic acid, and thirty-three lots were packaged in apackaging material having an inner surface made from LDPE. The filmswere all inspected after 3 weeks for stress cracking. The twopopulations were then compared using a 2 sided test. The results areshown in Table 4. The value of 0.005 for p indicates a high probabilitythe data sets are different populations.

TABLE 4 Results of t test on populations Packaging Material Defect RateEthylene acrylic acid Mean 8.38% SD  6.3% LDPE Mean 2.01% SD  1.4% p0.005

Example 6 Comparative Testing

Samples from 22 lots of film, all including PEO as polymeric component,were packaged in a packaging material including an inner surface madefrom ethylene acrylic acid and samples from 32 lots of film, eachincluding PEO as polymeric component, were packaged in a packagingmaterial including an inner surface made from LDPE. The films wereinspected at different times after packaging. The data is shown in FIG.3. To more clearly differentiate the rate of stress cracking at theearlier times, a second plot (FIG. 4) shows data obtained after 60 days.

Example 7

Film strips were individually packaged in foil/PET laminate pouches.Some of the product was heat annealed by placing the sealed pouches ofproduct in an oven at 70 degrees ° C. for 25 minutes. The product wasthen inspected over time for stress cracking. For each week (postpackaging) 2000 samples were opened and inspected. The results are shownin Table 5.

TABLE 5 Comparison of stress cracking in annealed and not annealed filmWeek 2 Week 3 Week 4 Lot A, not annealed  0.9%  3.3%  4.0% Lot A,annealed 0.00% 0.00% 0.00% Lot B, not annealed  1.0%  8.4%  5.7% Lot B,annealed 0.25% 0.00% 0.00%Based upon the data in Table 5, it is apparent that not annealedmaterial consistently has more stress cracking than the annealedproduct, which exhibits essentially no stress cracking or minimal stresscracking.

Example 8

Fresh (1 week old) and old (3 month old) of individual film stripspackaged in a foil/PET laminate pouch were examined using a Hinds nearinfrared birefringence systems using a measurement wavelength of 1310nanometers. This wavelength surprisingly showed anisotropic andisotropic changes while other birefringence instruments and wavelengthswere not able to see any birefringence. Mild heating at 70° C. for 1hour surprisingly resulted in a complete reduction of the stress as isapparent from comparing the 2D birefringence map before anneal (top:Fresh, Bottom: Old) shown in FIG. 7 to the 2D birefringence map afteranneal (top: Fresh, Bottom: Old) shown in FIG. 8. The yellow and redareas indicate higher internal stress while the green indicates thelowest stress. It is evident from this experiment that both old andfresh films exhibit internal stress before the annealing process andthat heat annealing lowers the internal stress of both the fresh and oldsamples.

Example 9

A film in accordance with the present invention is coated onto asubstrate and dried in accordance with drying methods as disclosed inU.S. Pat. Nos. 7,425,292, 7,666,337, and 7,357,8912. Before, during orafter slitting, the film is continuously delaminated from the substrate,heated to an annealing temperature, preferably 70 degrees C. (range of40-90 degrees) for a period of 10 minutes (range 0.5-60 minutes) andrewound onto a substrate. The film is then cut and packaged on standardpackaging machine into any type of packaging material.

What is claimed is:
 1. A package for storing pharmaceutical activecontaining film product, comprising: (a) a top layer having an innersurface and an outer surface; and (b) a bottom layer having an innersurface and an outer surface, said inner surface of said bottom layercomprising at least one polymeric material having at least one physicalcharacteristic selected from the group consisting of: (i) a surfaceenergy as measured by a water contact angle test of about 100 degrees orgreater; (ii) a surface adhesivity level of less than about 0.25 lbf asmeasured by a peel force testing using a load frame and packaging tape;and (iii) a surface RMS roughness of less than 800 nm as measured byatomic force microscopy at a 100 micron square sample size level;wherein said inner surface of said top layer is partially sealed to saidinner surface of said bottom layer, forming a pocket between said toplayer and said bottom layer.
 2. The package of claim 1, wherein saidinner surface of said top layer comprises at least one polymericmaterial having at least one physical characteristic selected from thegroup consisting of: (i) a surface energy of about 100 degrees orgreater, as measured by a water contact angle test; (ii) a surfaceadhesivity level of less than about 0.25 lbf as measured by a peel forcetest using a load frame and packaging tape; and (iii) a surface RMSroughness of less than 800 nm as measured by atomic force microscopy ata 100 micron square sample size level.
 3. The package of claim 1,further comprising a pharmaceutical active containing film productwithin said pocket.
 4. The package of claim 3, wherein said film productcomprises polyethylene oxide.
 5. The package of claim 4, wherein saidfilm product further comprises a second polymeric material differentfrom polyethylene oxide.
 6. The package of claim 1, wherein said surfaceadhesivity level of said inner surface of said bottom layer is less thanabout 0.20 lbf as measured by a peel force test using a load frame andpackaging tape.
 7. The package of claim 1, wherein said surface RMSroughness of said inner surface of said bottom layer is less than about700 nm as measured by atomic force microscopy at a 100 micron squaresample size level.
 8. The package of claim 2, wherein said surfaceadhesivity level of said inner surface of said top layer is less thanabout 0.20 lbf as measured by a peel force test using a load frame andpackaging tape.
 9. The package of claim 2, wherein said surface RMSroughness of said inner surface of said top layer is less than about 700nm as measured by atomic force microscopy at a 100 micron square samplesize level.
 10. The package of claim 1, wherein less than 5% of filmsstored in said package exhibit stress cracking after storage of threemonths at about room temperature.
 11. A method of packaging apharmaceutical active containing film strip comprising the steps of: (a)forming a pharmaceutical active containing film strip; (b) providing apackage, said package comprising: (i) a top layer having an innersurface and an outer surface; and (ii) a bottom layer having an innersurface and an outer surface, said inner surface of said bottom layercomprising at least one polymeric material having at least one physicalcharacteristic selected from the group consisting of: (1) a surfaceenergy of about 100 degrees or greater, as measured by a water contactangle test; (2) a surface adhesivity level of less than about 0.25 lbfas measured by a peel force testing using a load frame and packagingtape; and (3) a surface RMS roughness of less than 800 nm as measured byatomic force microscopy at a 100 micron square sample size level;wherein said top layer and said bottom layer form a pocket therebetweenwhen placed on top of each other; (c) placing said film strip withinsaid pocket; and (d) sealing said top layer to said bottom layer so asto provide a hermetically sealed pocket.
 12. The method of claim 11,wherein said inner surface of said top layer comprises at least onepolymeric material having at least one physical characteristic selectedfrom the group consisting of: (i) a surface energy of about 100 degreesor greater, as measured by a water contact angle test; (ii) a surfaceadhesivity level of less than about 0.25 lbf as measured by a peel forcetest using a load frame and packaging tape; and (iii) a surface RMSroughness of less than 800 nm as measured by atomic force microscopy ata 100 micron square sample size level.
 13. The method of claim 11,wherein said film strip comprises polyethylene oxide.
 14. The method ofclaim 13, wherein said film product further comprises a second polymericmaterial different from polyethylene oxide.
 15. The method of claim 11,wherein said surface adhesivity level of said inner surface of saidbottom layer is less than about 0.20 lbf as measured by a peel forcetest using a load frame and packaging tape.
 16. The method of claim 11,wherein said surface RMS roughness of said inner surface of said bottomlayer is less than about 700 nm as measured by atomic force microscopyat a 100 micron square sample size level.
 17. The method of claim 12,wherein said surface adhesivity level of said inner surface of said toplayer is less than about 0.20 lbf as measured by a peel force test usinga load frame and packaging tape.
 18. The method of claim 12, whereinsaid surface RMS roughness of said inner surface of said top layer isless than about 700 nm as measured by atomic force microscopy at a 100micron square sample size level.
 19. The method of claim 11, whereinless than 5% of film strips stored in said package exhibit stresscracking after storage of three months at about room temperature.